p21 restricts influenza A virus by perturbing the viral polymerase complex and upregulating type I interferon signaling

Chao Ma, Yuhan Li, Yanan Zong, Tony Velkov, Chenxi Wang, Xinyu Yang, Ming Zhang, Zhimin Jiang, Haoran Sun, Qi Tong, Honglei Sun, Juan Pu, Munir Iqbal, Jinhua Liu, Chongshan Dai, Yipeng Sun

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11 Citations (Scopus)


Many cellular genes and networks induced in human lung epithelial cells infected with the influenza virus remain uncharacterized. Here, we find that p21 levels are elevated in response to influenza A virus (IAV) infection, which is independent of p53. Silencing, pharmacological inhibition or deletion of p21 promotes virus replication in vitro and in vivo, indicating that p21 is an influenza restriction factor. Mechanistically, p21 binds to the Cterminus of IAV polymerase subunit PA and competes with PB1 to limit IAV polymerase activity. Besides, p21 promotes IRF3 activation by blocking K48-linked ubiquitination degradation of HO-1 to enhance type I interferons expression. Furthermore, a synthetic p21 peptide (amino acids 36 to 43) significantly inhibits IAV replication in vitro and in vivo. Collectively, our findings reveal that p21 restricts IAV by perturbing the viral polymerase complex and activating the host innate immune response, which may aid the design of desperately needed new antiviral therapeutics.

Original languageEnglish
Article numbere1010295
Number of pages26
JournalPLoS Pathogens
Issue number2
Publication statusPublished - Feb 2022
Externally publishedYes

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